A study out of Cornell University made the news recently when Maureen Hanson's team found distinct alterations in the gut flora of patients with ME/CFS. The headlines trumpeted the "first" biological marker for the disease in the microbiome.

Those of us who have kept track of the research know that this is not a "first." De Meirleir, Maes, Lemle, as well as Dunstan, and Butt in Australia have all published papers documenting alterations in gut flora in patients with ME/CFS (not to mention Lipkin and Hornig's huge Microbe Discovery Project). Those alterations laid the groundwork for Butt's successful treatment of ME with fecal transplants in the late 90s.

The question that needs to be asked is whether these alterations are the cause or the result of the disease. Every disease produces alterations in gut flora - diabetes, Crohn's, heart disease, HIV, and cancer are among them, as well as all infections. (For a good paper on this topic go HERE.) The gut, which is the seat of your immune system, responds instantly to pathogens. It even changes in accord with what you are eating withing a few hours.

But rather than chicken or egg, these gut changes could be chicken and egg. For example, the pathogen that causes ME results in changes to the microbiome, then subsequent chronicity due to an altered immune system results in a perpetuation of microbiome changes. These, in turn, lead to more chronicity as commensal bacteria enter the bloodstream.

It's a good model, even if it doesn't identify the original culprit that started this chain of events.

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn't alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

"Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn't normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease," said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper's senior author. "Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin."

"In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease," said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn's disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

A new study of mitochondrial DNA in ME/CFS patients has provided some important clues as to the variation of symptoms seen in patients.

Four important points brought out in this study were:

1) None of the patients showed any evidence of a mitochondrial genetic disease.

2) No difference was seen in the types of mitochondrial DNA between patients and healthy individuals

3) There was no increased susceptibility to ME/CFS among people with different mitochondrial SNPs (single variations in DNA)​4) However, there were associations of SNPs with certain symptoms and/or their severity. Individuals that carry a particular SNP, for example, are predicted to be at greater risk of experiencing particular types of symptoms once they become ill. (Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the most common type of genetic variation among people.)

What this means is that 1) ME/CFS is not genetic, 2) ME/CFS patients do not have pre-dispositions for getting the disease, and 3) there may be a single pathogen causing the disease.

The authors conclude:

"A puzzling aspect of ME/CFS has been the diversity of symptoms and the variation of their severity among different individuals. These differences should not be taken as proof that more than one insult was the initiating factor, nor that different patients have different underlying problems. It remains possible that much of the diversity of the manifestation of the illness results from genetic diversity rather than the existence of multiple fundamental causes."

This study provides a rationale for outbreaks and clusters. It also accounts for both the discrepancies in Fukuda, CCC, and ICC clinical case definitions as well as the large number of possible combinations of symptoms. These case definitions may be describing the same illness, caused by the same pathogen, as it is experienced by people with distinct genetic variations.

The findings of this study represent a major shift in thinking, not just about ME/CFS, but about all diseases. This study explains how a single pathogen can create multiple symptoms, and how those symptoms may manifest themselves depending on genetic variations in the host. The findings also may account for ranges in severity.

Patients with ME/CFS experience a profound lack of energy, severe fatigue, along with a variety of other symptoms, including one or more of the following: muscle pain, headaches, gastrointestinal discomfort, difficulty concentrating, exacerbation of symptoms following exercise, abnormal regulation of blood pressure and heart rate, and unrefreshing sleep. Mitochondria, sub-cellular organelles are responsible for producing ATP, the energy coinage of the cell, through conversion of glucose. Therefore, a logical approach to learn more about a disease affecting energy is probing of the function of mitochondria.

Mitochondria are made up of molecules encoded by the nuclear genome--DNA located in the nucleus--as well as the mitochondrial genome—a small amount of DNA present within each organelle. Defects in mitochondrial DNA lead to devastating genetic diseases, with such symptoms as brain abnormalities, severe fatigue, blindness or defective heart function—and can be fatal. The mitochondrial genome of healthy humans also exhibits some natural variation—a single component of the mitochondrial DNA sometimes differs between one human and another—this is known as a SNP (single nucleotide polymorphism, "snip"). Often more than one SNP differs between one population of humans and another—for example, mitochondrial genomes whose origin can be traced to France differ in a number of SNPs from those in people in Central Asia. These different types of mitochondrial genomes, based on a specific set of SNPs, are referred to as haplogroups. Even people whose mitochondrial DNA belongs to the same haplogroup can differ among one another because of some variation in additional SNPs. Some mitochondrial SNPs have been associated with various characteristics, such as adaptation to cold weather or high altitude environments and have been implicated in susceptibility to diabetes and various inflammatory diseases. Aninformative review of the role of mitochondria in disease has been written by Wallace and Chalkia, researchers at the University of Pennsylvania.

A further complexity of mitochondrial genetics is that there are many individual mitochondria within the same cell, and thus many copies of mitochondrial DNA in each cell. Sometimes new mutations arise so that some of the copies of DNA within the same cell, and therefore within the same person, differ from one another. This situation is called “heteroplasmy”. As cells grow and multiply, by chance there can be uneven distribution of normal vs. abnormal DNA to different cells. If mitochondrial DNA with a harmful mutation becomes the predominant type in a particular tissue, serious symptoms will emerge.

In our JTM paper, work that was primarily supported by the Chronic Fatigue Initiative, we sequenced the mitochondrial DNA from a cohort of ME/CFS patients and healthy individuals, using DNA extracted from white blood cells stored in the biobank developed by the Chronic Fatigue Initiative.

We asked four primary questions:

Were any of the ME/CFS patients identified by 6 well-known ME/CFS experts misdiagnosed and are actually victims of a mitochondrial genetic disease?

Do people with ME/CFS carry more copies of mitochondrial DNA with harmful mutations than healthy people (heteroplasmy)?

Are people belonging to one haplogroup more likely to fall victim to ME/CFS than another?

Are people who have particular SNPs more likely to experience particular symptoms or have increased severity of symptoms?

Our work showed that none of the blood samples obtained from 193 patients identified by the CFI’s 6 expert M.D.s gave any indication of a mitochondrial genetic disease.

Furthermore, we found no difference in the degree of heteroplasmy between patients and healthy individuals.

We also observed no increased susceptibility to ME/CFS among individuals carrying particular haplogroups or SNPs within a haplogroup.

However, we did detect associations of particular SNPs with certain symptoms and/or their severity. For example, we did find that individuals with particular SNPs were more likely to have gastrointestinal distress, chemical or light sensitivity, disrupted sleep, or flu-like symptoms. This finding does NOT mean that if your mitochondrial DNA carries one of these SNPs, you will inevitably experience a particular symptom or have higher severity of some symptoms. Instead, because a particular SNP was seen more often in ME/CFS patients with certain characteristics, individuals that carry that SNP are predicted to be at greater risk of experiencing particular types of symptoms once they become ill.

This study demonstrates the importance of a well-characterized cohort of patients and controls along with detailed clinical information about their experience of illness. Without the data from the lengthy patient questionnaires collected along with the subject’s blood, we could not have correlated SNPs with patient characteristics. While the materials from the CFI subjects are extremely valuable and our results are statistically significant, greater numbers of subjects must be analyzed to determine whether the correlations we detected continue to hold up when more patients are studied, and whether such correlations exist within people carrying other haplogroups.

Due to the European origin of most of the ancestors of the CFI subjects, most belong to haplogroup H, the most common European haplogroup. A much larger number of haplogroup H subjects, as well as large cohorts of individuals with other haplogroups, will be necessary to analyze to dissect out other possible correlations or to determine whether or not any of the correlations we detected with a relatively small population are spurious. With more subjects, we might also be able to detect additional correlations that were not obvious from our initial study.

Whether or not the genetic correlations we have observed are verified or not through further work, our study indicates an important hypothesis that should be tested in ME/CFS. How much of the variation in symptoms between different individuals results from their different nuclear and/or mitochondrial genetic makeup, rather than variation in the inciting cause?

A puzzling aspect of ME/CFS has been the diversity of symptoms and the variation of their severity among different individuals. These differences should not be taken as proof that more than one insult was the initiating factor, nor that different patients have different underlying problems. It remains possible that much of the diversity of the manifestation of the illness results from genetic diversity rather than the existence of multiple fundamental causes.

Sudden Onset has produced another excellent video explaining the science of ME/CFS.

In ME/CFS: The Scientific Evidence -Episode 3 - "The SIGNATURE" Mady Hornig's research on immune abnormalities is elegantly explained using images and music. I would encourage everyone to watch this 15-minute video, as you will not find a more concise explanation anywhere.

Mady Hornig's cytokine study, Distinct plasma immune signatures in ME/CFS are present early in the course of illness, made headlines last February for a number of reasons. First, it showed significant immune system alterations between patients and healthy controls. Second, it revealed why many other studies have not found similar abnormalities.

The answer turned out to be something fairly simple. The immune systems of people who had ME/CFS for three years (or less) had a cytokine pattern (a "signature") that was markedly different from controls as well as from patients who had been ill more than three years.

Based on these findings, the researchers concluded that people with short-term ME/CFS have upregulated immune systems indicative of a viral infection, and patients with long-term ME/CFS suffer from "immune exhaustion."

What was remarkable about this study was that not just one, but ALL twenty-four cytokines were altered in both long- and short-term patients compared to controls.
​
The early phase (blue bars) of ME/CFS showed elevations of nearly all the interleukins (pro-inflammatory cytokines) which is typical of an immune system fighting off an infection. Strikingly, patients who had been ill for less than a year were 100 times more likely to have elevated interferon gamma, which is indicative of a viral infection. Short-term patients were also 50% more likely to have elevated IL-12 P40, which is a pro-inflammatory cytokine produced by microglial cells (among others). The microglia are activated in the brain when there is an infection in the central nervous system. Although an elevation of IL-12 P40 is not definitive proof of neuroinflammation, it supports a study published in 2014 by Nakatomi et al. which found evidence of microglial activation in the brains of patients with ME/CFS.

The chronic phase (red bars) showed elevations in eotaxin CCL11, GMCSF (granulocyte macrophage colony-stimulating factor receptor), PDGF-BB (platelet-derived growth factor-BB ), and CD40L. Also of note was the depression of IL-17F in both phases. (In 2008, Metgzer et al. found a similar depression of IL-17F. The authors concluded that this cytokine may play a protective role against the disease. )

Because they perform so many roles, it is impossible to make generalizations about the function of individual cytokines. Nonetheless, three of the cytokines related to the chronic phase of ME/CFS stand out.

Eotaxin CCL 11 recruits eosinophils, white blood cells which are elevated in people with allergies. When administered to mice, eotaxin CCLL decreases their neurogenesis and cognitive performance.

GMCSF is found in high levels in joints with rheumatoid arthritis, an autoimmune disease.

At this point, a replication of this study is crucial. We can only hope that the NIH will undertake funding for similar immune system research.

It would also be enormously helpful if the authors of previous immune system (and other) studies went back over their data to see if there are patterns associated with short- and long-term patients which may have been lost when the results were averaged. Among the 5000+ studies that have been performed on ME/CFS patients there is a wealth of data that have yet to be explored.

A University of Leicester research team has discovered a vision-related abnormality that could help diagnose ME/CFS.

The abnormality, called "pattern glare," produces distortions, such as curving, wavering, and colors, when viewing stripes. Pattern glare has been associated with migraines and Irlen Syndrome (a visual processing disorder). It can lead to headaches, photophobia, and eyestrain.

This is not the first study to find a correlation between visual disturbances and ME/CFS. In May 2014, an Australian group found a greater occurrence of Irlen Syndrome in ME/CFS patients (Loew et al. "Symptoms of Meares-Irlen/Visual Stress Syndrome in subjects diagnosed with Chronic Fatigue Syndrome.")

A previous Australian study found significant variations in blood lipids as well as urine amino and organic acids in ME/CFS patients with Irlen Syndrome. They proposed that ocular symptoms might be caused by activation of the immune system due to "some infective agent." (Robinson et al. "A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: Speculation concerning immune system dysfunction.")

Coincidentally, I had an eye exam shortly before University of Leicester mstudy was published. On viewing a cross-hatch pattern, I remarked that it had blue horizontal stripes, and purple vertical stripes. "It's black and white," said the technician.

Both of my children have pattern glare - one has migraines, and the other Irlen Syndrome. ___________________________

Visual stress could be a symptom of Chronic Fatigue Syndrome, research suggests

Press Release: University of Leicester, November 24, 2015. People suffering from Chronic Fatigue Syndrome (CFS) could experience higher levels of visual stress than those without the condition, according to new research from the University of Leicester.

CFS, also known as Myalgic Encephalomyelitis (ME), is a condition that causes persistent exhaustion that affects everyday life and doesn't go away with sleep or rest. Diagnosis of the condition is difficult as its symptoms are similar to other illnesses.

A research team from the University of Leicester led by Dr Claire Hutchinson from the Department of Neuroscience, Psychology and Behaviour has examined patients with and without CFS and has found that those suffering from the condition are more vulnerable to pattern-related visual stress, which causes discomfort and exhaustion when viewing repetitive striped patterns, such as when reading text.

The results of the study, which is published in the journal Perception, could help in the diagnosis of CFS, as the findings suggest that there are visual system abnormalities in people with ME/CFS that may represent an identifiable and easily measurable behavioural marker of the condition.

Dr Hutchinson explained: "Diagnosis of ME/CFS is controversial. With the exception of disabling fatigue, there are few definitive clinical features of the condition and its core symptoms, overlap with those often prevalent in other conditions. As a result, ME/CFS is often a diagnosis of exclusion, being made as a last resort and possibly after a patient has experienced a series of inappropriate treatments of misdiagnosed disorders.

"It is imperative therefore that research focuses on identifying significant clinical features of CFS/ME with a view to elucidating its underlying pathology and delineating it from other illnesses. Doing so will help researchers and healthcare professionals gain important insights into the condition, aid diagnosis and, in the longer term, inform evidence-based therapeutic interventions."

The study assessed vulnerability of ME/CFS patients to pattern-related visual stress using a standardised test called the pattern glare test, in which people report the number of visual distortions they experience when looking at three repetitive striped patterns of different levels of detail.

During the study twenty patients with CFS and twenty patients without the condition were recruited.

Participants viewed 3 patterns, the spatial frequencies (SF) of which were either 0.3 (low-SF), 2.3 (mid-SF) and 9.4 (high-SF) cycles per degree (c/deg). They then reported the number of distortions they experienced when viewing each pattern.

Patients with ME/CFS reported more distortions on the intermediate striped pattern (Pattern 2) than people without the condition.

Dr Hutchinson added: "The existence of pattern-related visual stress in ME/CFS may represent an identifiable and easily measurable behavioural marker of ME. This could, in conjunction with other diagnostic tests, help delineate it from other conditions."

The work was funded by ME Research UK who provided funding for a 1-year MPhil studentship, awarded to Rachel Wilson, who was supervised by Drs Claire Hutchinson and Kevin Paterson from the University of Leicester's Department of Neuroscience, Psychology and Behaviour.

Dr Neil Abbot, Research & Operations Director at ME Research UK, added: "Around three-quarters of people with ME/CFS report a range of eye and vision-related symptoms that interfere with their everyday lives, yet there has been very little scientific investigation of the problem.

"Dr Claire Hutchinson and her team have previously confirmed the existence of eye movement difficulties in ME/CFS patients, and that symptoms, including eye pain, can be severe. Her new report in Perception extends these findings and raises the possibility that vision anomalies, including pattern-related visual stress, may have a diagnostic role in the disease."

The objective of this study was to determine vulnerability to pattern-related visual stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 20 ME/CFS patients and 20 matched (age, gender) controls were recruited to the study. Pattern-related visual stress was determined using the Pattern Glare Test. Participants viewed three patterns, the spatial frequencies (SF) of which were 0.3 (low-SF), 2.3 (mid-SF), and 9.4 (high-SF) cycles per degree (c/deg). They reported the number of distortions they experienced when viewing each pattern. ME/CFS patients exhibited significantly higher pattern glare scores than controls for the mid-SF pattern. Mid-high SF differences were also significantly higher in patients than controls. These findings provide evidence of altered visual perception in ME/CFS. Pattern-related visual stress may represent an identifiable clinical feature of ME/CFS that will prove useful in its diagnosis. However, further research is required to establish if these symptoms reflect ME/CFS-related changes in the functioning of sensory neural pathways.

Rivka Solomon is a long-time advocate for ME/CFS patients. She has been ill for 25 years, and has been witness to the many changes - political and social - affecting the patient community over the past two decades. On November 2, WBUR published her reaction to NIH's promise to increase funding for ME/CFS research.

Reprinted with permission.

Often Bedridden For 25 Years, Advocate Welcomes NIH Move On Fatigue Syndrome

Last week, the National Institutes of Health announced a welcome change: They promised to help the more than 1 million Americans who have the devastating disease commonly known as chronic fatigue syndrome.

This is akin to the NIH finally recognizing multiple sclerosis or Parkinson’s disease, two other debilitating neurological illnesses that also have no known cause or cure.

The name chronic fatigue syndrome, which trivializes the true horrors of the disease, was adopted by the government decades ago and has been truly detrimental to the patients. The stigmatizing name has allowed doctors, the media and even families whose loved ones got sick to dismiss patients as mere lazy malingerers.

After all, who isn’t fatigued in today’s hustle and bustle world? Take a nap. Get over it. Exercise it away.

Well, I tried. But napping didn’t help, and exercise made me significantly sicker.

So for the last 25 years in which I have had myalgic encephalomyelitis, or ME — the name the World Health Organization uses and the name most patients prefer — I have been forced to spend much of my life in or near bed.

Try doing that for a quarter of a century.

Myalgic encephalomyelitis means, literally, pain and inflammation of the brain and spinal cord. But what does that translate to in the real world? I often struggle with exhaustion so crushing it is hard to get to the bathroom, let alone lift my arms to shampoo my hair; brain fog so thick that formulating and finishing thoughts is a struggle; vertigo that makes it hard to see or stand up straight; numb hands; Jello-like legs; joint and muscle pain; and a hyper sensitivity to chemicals and perfumes that turns me into a canary in the coal mine.

The hallmark of the disease, though, is the inability to exert any energy — physical or intellectual — without a relapse or flare of unknown length. Sometimes it can take days or weeks to regain my strength after a phone conversation. It is as if my body can’t replace the cellular energy required to do, well, just about anything.

All this came on after mono. That was all it took. Mononucleosis. Other patients have gotten myalgic encephalomyelitis/chronic fatigue syndrome — abbreviated as ME/CFS — from other assaults that apparently slapped down their immune systems, too, and/or triggered an autoimmune response. The result? With no commonly accepted diagnosis and no FDA-approved treatments, many of us have been languishing for years.

Then, in 2014 and 2015, the NIH sponsored two initiatives: a report generated by the Pathways to Prevention program and a report from the prestigious Institute of Medicine. Between the two, they found ME/CFS was a serious disease that can significantly impair the lives of those who get it. They also found that research into ME/CFS was seriously underfunded and there is an urgent need to invest in it.

How true.

For years, the NIH has been allocating a pittance to ME/CFS research. This is most strikingly seen when compared to other neuro-immune diseases. Multiple sclerosis, with 400,000 U.S. patients, gets funded $102 million per year. ME/CFS, with more than 1 million U.S. patients, gets a paltry $5 million per year. The NIH gives more money to research on hay fever than ME/CFS. And yet people with hay fever don’t spend decades in bed, too weak to function.

The question is why?

Why, in the past 30 years, when ME/CFS reared its ugly head on the American scene and we were given the moniker of chronic fatigue syndrome (that’d be like calling Parkinson’s “shaky person’s syndrome”), did the government ignore us? Worse, why did they delegitimize, marginalize and psychologize this disease by funding studies to supposedly show we have personality disorders, a fear of leaving our homes or childhood trauma? (Yes, these are real studies.) Why tell us exercise will help, when that would be like giving sugar to a person with diabetes?

Perhaps they wanted to spare insurance companies the expense of treating us? Perhaps leadership at the National Institutes of Health had a bias against us? Or perhaps governments only respond to pressure; and with the patients so sick there are few who can lobby on Capitol Hill or demonstrate in the streets, such as the highly effective HIV/AIDS activists from ACT UP.

But with last week’s NIH press release promising to bolster ME/CFS research, the tide is turning.

Surely, the years of patient advocates struggling, often from bed, to get the government’s attention made an impact. It was also likely personal relationships: The disease is now so prevalent that NIH Director Dr. Francis Collins has current and past employees with the disease, and top-notch scientist colleagues with family members too sick to feed themselves. All petitioned Dr. Collins for help.

Whatever turned the tide, I spent the day that the NIH put out its press release crying. I was relieved that my government was essentially acknowledging for the first time that ME/CFS is a serious disease with a profound unmet need. From bed, I typed frantically on my computer with others from the online patient community: Could it be, we asked each other, that with Dr. Collins’ promise of help, our own government may actually, finally, come to our rescue?

I have already lost my 30s, my 40s and some of my 50s to this disease. Could the end of my nightmare be in sight?

Dr. Collins, now is the time to attach a dollar sign to your promise of help. And please make it happen fast. We patients are petitioning for funding equity, making the funding commensurate with the burden of the disease and the population in need — that is, at least $250 million per year. I and at least 1 million other Americans, 17 million worldwide, can’t wait to get our lives back. The help can’t come soon enough.

All in all, it’s been an astonishing week full of hope for ME/CFS patients. We’ve had recognition and a promise of help from the U.S. government. And, like icing on the cake, a dogged investigative journalist, David Tuller, has taken on the single-most noted study upholding the idea that ME/CFS is a trivial condition that is all in our heads. See his article here: “Trial By Error: The Troubling Case Of The PACE Chronic Fatigue Syndrome Study.”

Finally, we ME/CFS patients are being taken seriously. What a welcome change.

Rivka’s Suggested Do’s And Don’t’s:

— Do have great compassion for those with ME/CFS.— Do ask how you can help and make offers of specific help, from vacuuming to cooking meals to rides to doctor’s appointments.— Do remember them, even if they have not been able to leave the house for weeks or months: Call and remind them you care.— Don’t think that ME/CFS is “all in their head.”— Don’t suggest they exercise when they can’t.— Don’t tell patients that you are tired too.

Rivka Solomon is a Massachusetts writer whose commentaries have been featured on WBUR. She created a women’s empowerment program, That Takes Ovaries, based on her book and play of the same name, and is now writing a book about her 25 years with ME/CFS and Lyme disease.

How long have we waited for the NIH to acknowledge that this is a serious disease that merits research?____________________​

Press Release: NIH, Thursday, October 29, 2015. The National Institutes of Health is strengthening its efforts to advance research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a disease for which an accurate diagnosis and effective treatment have remained elusive. The actions being taken include launching a research protocol at the NIH Clinical Center to intensely study individuals with ME/CFS and re-invigorating the efforts of the long-standing Trans-NIH ME/CFS Research Working Group with the National Institute of Neurological Disorders and Stroke (NINDS) as the lead of a multi-institute research effort.

“Of the many mysterious human illnesses that science has yet to unravel, ME/CFS has proven to be one of the most challenging,” said NIH Director Francis S. Collins, M.D., Ph.D. “I am hopeful that renewed research focus will lead us toward identifying the cause of this perplexing and debilitating disease so that new prevention and treatment strategies can be developed.”

NIH’s direction on the disease is being guided by a recent Institute of Medicine report External Web Site Policy, that recommended new diagnostic criteria and a new name for the disease (Systemic Exertion Intolerance Disease), and an NIH-sponsored Pathways to Prevention meeting External Web Site Policy that generated a position paper and report with recommendations for research strategies.

According to the Centers for Disease Control and Prevention, ME/CFS is estimated to affect more than 1 million Americans, and has been reported in people younger than 10 years of age and older than age 70. ME/CFS is an acquired, chronic multi-system disease characterized by systemic exertion intolerance, resulting in significant relapse after exertion of any sort. The disease includes immune, neurological and cognitive impairment; sleep abnormalities; and dysfunction of the autonomic system, which controls several basic bodily functions. These symptoms result in significant functional impairment accompanied by profound fatigue. Additional symptoms may include widespread muscle and joint pain, sore throat, tender lymph nodes and headaches. Effects of the illness can range from moderate to debilitating, with at least one-quarter of individuals with ME/CFS being bedbound or housebound at some point in the illness and many individuals never regaining their pre-disease level of functioning. Because the pathology of ME/CFS remains unknown and there is no test to diagnose the disease, studies to date have used different criteria for diagnosis, which has limited the ability to compare results across studies. Additionally, many of the published studies are based on small study populations and have not been replicated.

In an effort to remedy this situation, NIH will design a clinical study in the NIH Clinical Center with plans to enroll individuals who developed fatigue following a rapid onset of symptoms suggestive of an acute infection. The study will involve researchers from NINDS, the National Institute of Allergy and Infectious Diseases, National Institute of Nursing Research and National Heart, Lung, and Blood Institute. The primary objective of the study is to explore the clinical and biological characteristics of ME/CFS following a probable infection to improve understanding of the disease’s cause and progression.

NIH will also be considering additional ways to support ME/CFS research in the extramural research community. Since the root cause of ME/CFS is unknown and the manifestations of the disorder cut across the science interests of multiple NIH institutes and centers, a trans-NIH working group will be needed to assist that plan. NINDS Director Walter J. Koroshetz, M.D., will chair the Working Group along with Vicky Holets Whittemore, Ph.D., the NIH representative to the U.S. Department of Health and Human Services’ Chronic Fatigue Syndrome Advisory Committee. One goal of the group will be to explore how new technologies might shed light on what causes ME/CFS. The Working Group includes representation from 23 NIH institutes, centers and offices.

Last fall, Invest in ME announced an update in its research into the microbiome of ME/CFS patients. The study is based on the hypothesis that exposure to gut microbes through increased intestinal permeability (aka "leaky gut") initiates microbe-driven inflammatory reactions in ME/CFS. The researchers hope to detect increases in serum antibodies towards specific intestinal bacteria.

The goal of the study is "to determine if alterations in intestinal barrier function and/or microbiota firstly, exists in ME/CFS patients and secondly, whether there is an interaction between microbe-driven inflammatory responses and neuronal proteins."

As a hypothesis, this study has a firm foundation.

Antibodies produced by the infiltration of gut bacteria into the bloodstream can initiate, among other things, a cascade of potentially lethal inflammatory responses. In 2014, researchers at the University of Chicago found that patients in the Intensive Care Unit had only limited kinds of gut flora left in their intestines after multiple rounds of antibiotics. Not surprisingly, these were flora that were pathogenic (Candida, a yeast, and antibiotic-resistant Staph). What was more, once the normal flora had been killed off, these pathogens became deadly. Three of the ICU patients died - not from injuries or from infections - but from pathogenic gut flora.

Slow Sepsis

Dr. David Bell proposed that patients with ME/CFS have what he called "slow sepsis." In his monograph, Cellular Hypoxia and Neuro-Immune Fatigue, he suggests that ME/CFS is a slow, chronic form of septic shock. The sequence of events in septic shock is: 1) a serious infection, 2) production of cytokines, 3) increased nitric oxide, and 4) interference with the production of cellular energy. In severe cases of septic shock, the loss of cellular energy is so profound that it can be fatal.

Dr. Bell suggests that a similar sequence takes place in ME/CFS, but more gradually. In ME/CFS there is: 1) an initiating infection or toxic exposure, which 2) leads to immune activation, increasing the production of cytokines, 3) the increase in cytokines leads to the production of increased nitric oxide (NO), 4) NO increases peroxynitrite and superoxide, which leads oxidative stress, and interferes with mitochondrial function, 5) the cell becomes hypoxic (oxygen-starved), and 6) vasculopathies, neuropathies, and autoimmune processes develop.

While Dr. Bell does not propose that this sequence of events can be initiated by leaky gut, there is absolutely no reason to assume that it can't. The destruction of the tight juncture between the cells of the intestinal lining has a host of causes. Any infection in the intestines (e.g. enteroviruses, parasites), drugs (e.g. NSAIDs. steroids), viral infections, radiation therapy for cancer, nutrient deficiencies (e.g. zinc), inflammatory conditions, toxins, and antibiotics can lead to the production of excess NO (oxidative stress), compromising the integrity of the gut lining (Wu et al, 2002). Given the high level of oxidative stress found in people ME/CFS it is likely that the majority of patients will develop leaky gut.

Evidence of gut dysbiosis in ME/CFS

The involvement of intestinal flora in the perpetuation of ME/CFS is one that is backed by solid research.

Dr. Kenny De Meirleir found that gut dysbiosis correlates with cognitive dysfunction in people with ME/CFS. He discovered that in people with ME/CFS there are high levels of bacteria not normally found in gut flora, notably gram positive lactic acid bacteria. In addition, Dr. De Meirleir's team found active parvovirus B19 infections in the GI tracts of 40% of CFS/ME patients, as well as EBV and herpesvirus 6 in lesser amounts. Dr. John Chia has found a chronic form of enteroviral infection in the stomachs of ME/CFS patients, which he believes could lead to a variety of symptoms without causing direct organ damage.

In 2012, Michael Maes et al. published research indicating that translocation of bacteria due to increased intestinal permeability correlated with systemic inflammatory responses in ME/CFS patients. The researchers concluded that "translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients."

With the mounting evidence for GI infection, comprised gut lining, and translocation of gram-negative bacteria in patients with ME/CFS, it is imperative that research leading to treatment - such as the research conducted by Invest in ME - be supported.

Remedies for leaky gutWhile research that helps explain the mechanisms of ME/CFS is important, people who have leaky gut and "slow sepsis" need to find ways of fixing the problem without delay. Poisoning, however slow, has immediate immune system consequences that cannot be ignored.

Although there is no drug to cure leaky gut, there are supplements that have been proven to help heal the mucosa of the gut lining;

Zinc carnosine: A 2007 study by A Mahmood et al, found that zinc carnosine stimulates gut repair processes. (You can read the full study here.)

Fiber: There is considerable debate about whether insoluble fiber (cellulose) is better for restoring the gut lining than soluble fiber. Research supports the idea that insoluble fiber is better for intestinal health, and that large amounts of soluble fiber may actually impair gut health (Shiao and Chang, 1986). In any case, diets that do not contain fiber increase intestinal permeability (G Spaeth, 1990).

Essential fatty acids (EFAs): Essential fatty acids, such as fish oil, flaxseed oil and borage oil, can help repair injury to the lining of the gut and restore gut mucosa. EFAs also limit the harmful effects created by the translocation of endotoxins (gram-negative bacteria found in the large intestine) (Vanderhoof et al. 1991).

Antioxidants: In 2008, M. Maes and J.C. Leunis found that leaky gut in patients with ME/CFS could be corrected with natural anti-inflammatories and antioxidants. Some of the antioxidants that have been reported as helpful for leaky gut are: NAC, Glutathione, and Gamma oryzanol.

Butyrates: Butyrates (also called butyric acid) are short-chain fatty acids produced in the colon by the fermentation of carbohydates through the action of intestinal flora. Butyrates enable your gut to function. Without them, the cells that line your intestines die by autophagy (they eat themselves). Butryrates are found naturally in butter. They can also be taken as a supplement (ButyrEn).Further Reading:

Michael Maes and his colleagues have a long history of delving into immune system and mitochondrial abnormalities, not just in ME/CFS but in a number of diseases.

In this comprehensive article, they support the hypothesis that inflammation and subsequent mitochondrial disruption are features shared by several autoimmune diseases and neuroimmune disorders as well as ME/CFS.

The article below, which is fully available under a Creative Commons License, is the most comprehensive cross-illness review of inflammatory markers, mitochondrial dysfunction and oxidative stress that has been published to date. In it, the authors present research findings in MS, Lupus, Parkinson’s disease, major depression, ME and CFS. Their conclusion is that:" ... there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage."In their review of markers associated with CFS and ME, the authors point out that "elevated levels of TNF-α and IL-1B [pro-inflammatory cytokines] are, in fact, particularly commonplace observations in patients recruited into studies using the internationally agreed diagnostic guidelines." They also discuss abnormal muscle mitochondrial function and defective aerobic metabolism that are "uncharacteristic of muscle disuse" (i.e. deconditioning), as well as abnormal lactate production after exercise.

Neuroimaging studies reveal "considerable ... evidence demonstrating impaired blood flow in the cortex and cerebellum in many patients with a diagnosis of CFS." Additional studies show reductions in white and gray matter, hypometabolism of glucose (which transports oxygen to the brain), and astrocyte dysfunction CFS patients (astrocytes comprise 20%-40% of all glia in the brain, and help maintain the blood-brain barrier). The researchers ascribe all of these impairments to sustained inflammation.

At the end of their review, there are several suggestions for treatment of inflammation and oxidative stress due to inflammation, including Omega-3s, zinc, curcumin, CoQ10, N acetylcysteine, methylfolate and dimethyl fumarate._________________________________________

The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

Discussion

Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.

Summary

It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.___________________

Background

There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders [1,2]. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways [3-5]. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes [1,6] activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation [7,8]. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion [1,9,10]. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue.The existence of chronically activated immune and inflammatory pathways in the periphery and their causative role in the genesis of neuroinflammation has been established in a range of neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s and Parkinson’s disease [11-16]. Many individuals with neuroinflammatory and neurodegenerative diseases also suffer from fatigue. For example, upwards of 80% of multiple sclerosis patients suffer from fatigue [17]. A study by Beiske and Svensson reported that between 37% and 57% of patients with Parkinson’s disease also experience incapacitating fatigue [18]. Fatigue is one of the characteristics of major depression [19,20]. Chronic systemic inflammation and the presence of activated microglia are also found in patients with major depression [19-22]. Chronic systemic inflammation and immune activation is also an invariant finding in many patients diagnosed with chronic fatigue syndrome (CFS) even without evidence of increased pathogen load [17].

Severe chronic fatigue is also experienced by many people with an autoimmune disease. Thus, upwards of 67% of people with Sjogren's syndrome [23], 76% of patients with systemic lupus erythromatosis (SLE) [24] and 70% of people with rheumatoid arthritis [25] suffer incapacitating levels of fatigue. Peripheral systemic inflammation and immune activation, as evidenced by elevated levels of proinflammatory cytokines and other inflammogens, is seen in patients with rheumatoid arthritis [26,27], SLE [28,29] and Sjogren's syndrome [30,31]. It is interesting to note that neurological sequelae are seen in up to 80% of patients with SLE and 70% of patients with primary Sjögren's syndrome [32,33]. In addition, the presence of neuroinflammation, in the shape of activated microglia, has been confirmed in patients with SLE [34]. Neurological complications are also commonplace in patients with rheumatoid arthritis [35].The question arises as to the factors involved in creating a chronically activated immune system in these patients. While there is some evidence linking viral infections to the development of multiple sclerosis [36,37], the situation in Parkinson’s disease is different, where there is considerable evidence suggesting environmental toxins in the etiopathogenesis of the illness [38]. One of the key drivers in the development of chronic immune activation in the absence of bacteria or virus infection is the development of chronic inflammation as evidenced by elevated levels of cytokines and oxidative and nitrosative stress (O and NS) and characterized by activated NF-kappaB [6,39]. Indeed, the production of proinflammatory cytokines and other inflammatory molecules by macrophages and other sentinel cells, even in the absence of pathogen invasion, and the subsequent activation of NF-kappaB are early events in the genesis of chronic inflammation [40,41]. Activation of this transcription factor leads to the upregulation of cytokines and O and NS [6,42-44]. These players can engage in a feed-forward manner to maintain and amplify chronic inflammation and immune activation in a TLR radical cycle [4].

Briefly, elevated levels of proinflammatory cytokines can amplify the activity of NF-kappaB by stimulating the canonical pathway leading to a cycle of mutually elevated activity [45,46]. The relation between O and NS and NF-kappaB is a little more complex, but the upregulation of O and NS can directly increase the activity of NF-kappaB [47]. Moreover, O and NS may damage lipids, proteins and DNA, leading to the formation of redox-derived damage-associated molecular pattern molecules (DAMPs) [48,49]. Once formed, these redox-derived DAMPS engage with TLRs further amplifying production of NF-kappaB, cytokines and O and NS [4,50]. Hence, chronic inflammation and immune activation can be maintained and amplified by engagement of TLRs by DAMPS [4].

Chronically elevated levels of NF-kappaB, proinflammatory cytokines and O and NS, in turn, lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, which can further amplify the TLR-radical cycle by acting as a pathogen-associated molecular pattern (PAMP) [1]. Translocation of bacterial lipopolysaccharides (LPS) from the gut and engagement with TLRs, due to a state of increased intestinal permeability driven by the effector molecules of chronic inflammation is another cause of chronic immune activation that may play a role in major depression, CFS, neuro-inflammatory disorders and some systemic autoimmune disorders [6,7]. For example, further evidence of chronic immune activation in these neuroimmune and autoimmune illnesses is provided by data demonstrating TLR activation and upregulation in multiple sclerosis (MS) [51] and SLE [52].

Given the established association between chronic inflammation and the genesis of incapacitating fatigue [1], the TLR-radical cycle can potentially explain the development of incapacitating fatigue in patients suffering from these and other illnesses. This association may be explained by chronically increased levels of proinflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) produced by the TLR-radical cycle upon stimulation by PAMPs and DAMPs [4].

We have reviewed previously that some proinflammatory cytokines, including IL-1β, TNF-α and IL-6, and increased O and NS processes may cause fatigue in some vulnerable individuals [1,4,6,7]. Mitochondrial dysfunction likely plays a major role in the progression of MS. Electron transport chain (ETC) complex I, complex III and complex IV activity is grossly reduced in normal appearing gray matter and in normal tissue within the motor cortex in patients suffering from this illness [53,54]. There is also direct evidence of globally impaired energy production and longitudinal depletion of ATP levels leads to increased levels of physical disability [55].

Multiple lines of evidence demonstrate the existence of mitochondrial dysfunction in many, but by no means all, patients afforded a diagnosis of CFS [56]. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins [57,58]. Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse [59]. Several other teams have reported significant downregulation of oxidative phosphorylation in striated muscle [60,61]. Complex I deficiency is seen in the frontal cortex and substantia nigra of Parkinson’s disease patients [62], and this defect is also observed in peripheral tissues, such as skeletal muscle [63], strongly indicating a widespread reduction in complex I activity in Parkinson’s disease. Impaired complex III function has also been reported in the platelets and lymphocytes of patients with this illness [64]. There is also accumulating evidence that inflammation and subsequent mitochondrial dysfunction drive the symptoms of major depression [65,66].

Localized or global mitochondrial dysfunction is also an invariant feature of autoimmune diseases. Persistent mitochondrial membrane hyperpolarization and increased O and NS production combined with depleted levels of glutathione and ATP is an invariant characteristic of T cells in SLE [67,68]. The release of DAMPS into the systemic circulation, consequent to necrosis, acts as a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation which, in turn, amplifies mitochondrial dysfunction in a vicious feed-forward loop [56,69]. The association between chronic oxidative stress, systemic inflammation and mitochondrial dysfunction and chronic oxidative stress is also firmly established in Sjogren's syndrome [70]. There is also evidence of widespread nitric oxide (NO)-induced inhibition of complex III and V of the ETC in patients with rheumatoid arthritis [71,72]. The causative role of chronic inflammation and oxidative stress and mitochondrial dysfunction is explained by the presence of elevated levels of ROS and RNS in such environments.

These entities cause damage to proteins, DNA and lipid membranes [56]. NO and peroxynitrite have the capacity to inhibit crucial enzymes within the ETC and can inactivate crucial enzymes in the tricarboxylic acid cycle leading to, often critical, reductions in the generation of ATP [7]. Peroxynitrite, in particular, also has a destructive influence on the mitochondrial membrane leading to the loss of potential difference between the outer and inner membrane needed to manufacture ATP [7]. The products of lipid peroxidation driven by elevated levels of ROS are also toxic to mitochondrial membranes. It is noteworthy that inhibition of the ETC leads to the formation of even higher concentrations of oxygen radical species which, in turn, leads to further impairment of mitochondrial function [7]. Needless to say there are numerous studies demonstrating that the origin of severe intractable fatigue seen in people with syndromic mitochondrial diseases lies in mitochondrial pathology and depleted generation of ATP. The reader is referred to the work of [56] for further details.

In this narrative review we will review the evidence pertaining to the genesis of intractable debilitating fatigue in multiple sclerosis, Parkinson’s disease, SLE, Sjogren’s disease, rheumatoid arthritis, major depression and CFS with a view of forming a conclusion as to whether such evidence justifies the viewpoint that the debilitating fatigue commonly suffered by those patients diagnosed with various illnesses is immune, inflammation or O and NS-mediated either directly or indirectly by causing abnormalities such as mitochondrial dysfunctions and central, neuropathological or functional processes [56,73-75]. These specific disorders were selected as examples along a spectrum of imbalance involving various degrees of activation of immune-inflammatory and O and NS pathways, and mitochondrial and brain metabolic dysfunctions in systemic auto-immune, immune-inflammatory and neurodegenerative disorders. Figure 1 shows the underlying processes and pathways associated with secondary fatigue, which we will discuss in the following sections.

Fatigue is recognized as one of the most disabling and common symptoms of MS affecting up to 80% of sufferers [17,76,77]. Numerous studies have demonstrated that the Expanded Disability Status Score (EDSS) correlates positively with patient self-reported fatigue scores using a variety of fatigue scales in patients with MS [78-81].

Immune activation, chronic inflammation and mitochondrial dysfunction

Chronic activation of the peripheral immune system is a characteristic observation in MS patients. Many studies report elevated levels of activated Th17 and Th1 T cells, and impaired function of regulatory T cells [17,82,83]. The evidence demonstrating an associative relationship between chronic activation of the immune system and the genesis of neuroinflammation is strong in MS due to the proven effectiveness of rituximab [84] and natalizumab [85], which are monoclonal antibodies which primarily target leucocytes but significantly reduce objective markers of disease activity in the central nervous system (CNS) [86]. It is also noteworthy that increased levels of TNF-α in the periphery are often predictive of the development of active disease. Peripheral TNF-α levels are also predictive of disability levels as estimated by the EDSS [87-89]. Peripheral levels of this and other cytokines correlate positively with fatigue severity which affects the vast majority of people with this illness [17,90-92]. TLR4 receptors are also upregulated in the brain and peripheral immune system in patients with MS [93-95]. There is also copious evidence indicating that chronic systemic inflammation and oxidative stress play a causative role in the etiopathogenesis of MS [96-98]. Elevated markers of chronic inflammation and oxidative stress are found in the brain, cerebrospinal fluid (CSF) and various blood compartments [82,99]. Oxidative stress levels increase quite dramatically during relapses but drop to barely detectable levels in patients during the remission phase [100]. It is also noteworthy that levels of chronic inflammation and oxidative stress in the CSF and blood correlate positively and significantly with disability levels as estimated by EDSS [101,102]. Finally, the extent of gadolinium-enhanced lesions appears to correlate significantly and positively with levels of oxidative stress [102].

It appears that although the genesis of pathology in early disease is mainly driven by inflammation [103], mitochondrial dysfunction likely plays a pivotal role in disease progression. Oxidative damage to mitochondrial DNA and impaired complex 1 activity is a characteristic finding in active MS lesions [104], but complex I, complex III and complex IV activity is also reduced in normal appearing gray matter and in normal tissue within the motor cortex [53,54,105].The use of nuclear magnetic resonance (NMR) spectroscopy has found direct evidence of globally impaired energy production and increased lactate production in the CSF [106-108]. In a longitudinal study, progressive central depletion of ATP over a three year period correlated positively and significantly with increased indices of physical disability as measured by EDSS changes, which strongly suggests a global impairment of ATP synthesis in MS [108].

Neuroimaging and neuropathology

Until recently, all studies investigating the phenomena had failed to find any significant correlation between increasing self-reported fatigue during the performance of sustained cognitive tasks and changes in brain activity using any neuroimaging modality [109]. It has been argued that this situation has arisen because self-reported fatigue is not an objective or accurate indicator of cognitive performance in the first place [109]. However, the first evidence displaying a positive relationship between cognitive fatigue and changes in brain activity during a task was provided in a recent study [109]. While the relationship between self-reported fatigue and neuroimaging changes is still a matter of considerable debate, the positive association between changes in brain activity and objective measures of cognitive fatigue is generally accepted [110,111]. The bulk of evidence demonstrates that these changes in activity occur in several areas of the brain with most studies reporting this phenomenon in the basal ganglia and the prefrontal cortex [109].

Overall, the results of these studies have been interpreted as support for the hypothesis that the origin of fatigue seen in patients with MS and other neurological diseases arises as a result of failure of integrative processes within the basal ganglia which normally coordinate inputs from the limbic system and outputs to the motor cortex [109,112]. MS was once considered to be a disease of white matter but there is now overwhelming evidence that gray matter pathology occurs early in the disease often before the advent of white matter involvement [113,114]. Conventional magnetic resonance imaging (MRI) is of limited value in revealing gray matter pathology but newer MRI approaches based on FLAIR technology and NMR spectroscopy appear to display adequate sensitivity [114,115]. Gray matter atrophy occurs in very early stages of disease and is seen in people with clinically isolated syndrome (CIS) [115-117]. Indeed, this phenomenon is detected in people with first attack MS [118]. The extent of gray matter atrophy correlates significantly and positively with the degree of physical disability and cognitive impairment seen in many patients with this illness [119,120]. It is noteworthy that reduced gray matter perfusion is seen in very early disease without any loss of volume or other visible sign of gray matter (GM) pathology [121]. Cortical inflammation and metabolic abnormalities, such as reduced choline and N-acetyl aspartamine levels, are also evident in early MS without evidence of any kind of gray or white matter abnormalities [114,119,122]. Other studies, when viewed as a whole, have established a clear relationship between global or localized gray matter atrophy and hypoperfusion in the development of fatigue [123-126]. Other observations include an association between fatigue and glucose hypometabolism in the basal ganglia and frontal cortex [127-129] and a decreased N-acetyl aspartamine/creatine ratio in the basal ganglia, suggestive of gliosis [130].

Finally, Calabrese et al. reported a positive association between increased fatigue and widespread atrophy of the basal ganglia and prefrontal cortex [131]. It is tempting to speculate that these observations could arise from astrogliosis and underlying loss of astrocyte numbers and the normal regulatory functions of the surviving astrocyte population. Recent evidence indicates that reactive astrogliosis may play a major causative role in the development and progression of MS [132,133]. It is also worthy of note that astrocyte loss is a characteristic feature of this disease [134]. Protoplasmic astrocytes are primarily found in gray matter and form the vast bulk of cells located in this tissue [135]. These glial cells in particular have crucial roles in coordinating neurometabolic and neurovascular coupling and, hence, the delivery of oxygen and energy to neurons [136,137]. Given that astrocytes form the vast bulk of gray matter it seems likely that the loss of gray matter seen very early in the development of the disease is due to loss of astrocytes [138]. It is also interesting that the magnitude of gray matter loss correlates positively with severity of inflammation [138]. The presence of reactive astrogliosis would suggest that the regulatory performance of the remaining astrocytes could be compromised and, thus, would go some way to explaining the abnormalities in perfusion and glucose metabolism and the development of fatigue seen in these studies. This state of affairs could explain, in part, the regulatory dysfunction seen in the basal ganglia which seems to underpin the observations surrounding the changes in brain activity and the development of cognitive fatigue noted earlier.

Chronic fatigue syndrome

Fatigue in chronic fatigue syndrome

Pathological levels of fatigue unrelated to activity and not relieved by rest is a mandatory requirement for a diagnosis of chronic fatigue syndrome under the current internationally accepted diagnostic guidelines [139]. The original diagnostic criteria contained another mandatory element, namely a clinical picture whereby the patient’s global symptoms represent a unitary illness with a single pathogenesis and pathophysiology.It is more likely that a diagnosis of CFS represents a spectrum of illnesses where different pathophysiological processes converge to produce a very similar phenotype [140]. Hence, any information regarding immune abnormalities, chronic inflammation, mitochondrial dysfunction and neuroimaging should be viewed with these issues in mind [141]. (Emphasis added.)

Immune activation, chronic inflammation and mitochondrial dysfunction

Numerous research teams have reported a wide range of peripheral immune abnormalities in people afforded a diagnosis of CFS [1,142,143]. The presence of circulating activated Th1, Th2 and Th17 T cells have all been detected. Recent evidence has challenged the view that people with CFS display immune abnormalities consistent with a Th2 pattern of T cell differentiation, and now data reveal that while some patients present with a Th2 profile and a preponderance of anti-inflammatory cytokine production, others present with a Th1 or possibly Th17 profile, with the synthesis of proinflammatory cytokines being dominant [144-146]. Elevated levels of TNF-α and IL-1B are, in fact, particularly commonplace observations in patients recruited into studies using the internationally agreed [139] diagnostic guidelines [144,147-151]. We have reviewed previously that patients with CFS and Myalgic Encephalomyelitis (ME) show different cytokine profiles, for example, a Th1-like pattern, with increased levels of IFN-γ, IL-2, IL-12 and IL-2 receptor, or a Th2-like pattern, with increased levels of IL-10, IL-4 and IL-5, or combinations thereof [1]. Two recent studies reported evidence of activated TLR4 receptors [152-154].The causative relationship between chronic inflammation and the development of fatigue is perhaps strongest in patients afforded a diagnosis of CFS, with many studies demonstrating a significant positive correlation between surrogate markers of inflammation, oxidative stress and symptom severity [17,155-159]. (Emphasis added)Miwa and Fujita (2010) demonstrated that a rapid decline in inflammation and oxidative stress of patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile [160]. Markers of chronic inflammation and oxidative imbalance have also been detected in skeletal muscle and levels of oxidative stress in this patient population correlated positively with objective measures of muscle fatigability [161]. Numerous authors have reported abnormalities consistent with mitochondrial dysfunction in patients afforded a diagnosis of CFS [56]. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins [57,58,162].

Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse [59,163]. Several other teams utilizing 31-P NMR spectroscopy have reported significant down regulation of oxidative phosphorylation [60,61,164-167]. Other studies reported the presence of abnormal lactate responses to exercise indicative of a shift to glycolytic energy generation in at least some patients with a CFS diagnosis [168]. In a recent review, Filings and others [169] conclude that there was ample evidence of mitochondrial dysfunction and impaired bioenergetics performance in patients afforded a diagnosis of CFS, but once again it was confined to patients diagnosed according to internationally agreed criteria and not apparent in all patients [169].

Defects in oxidative phosphorylation and ATP generation have also been revealed in exercise testing with the pattern of physiological responses being characteristic of mitochondrial dysfunction [170]. Exercise performance was examined in a cohort of CFS patients and a loss in the linear relationship between heart rate and cardiac output and the dissipation of oxygen concentration gradient between venous and arterial blood characteristic of mitochondrial dysfunction was reported [171]. Finally, authors ultilizing NMR spectroscopy have reported that some patients with CFS display significantly elevated ventricular lactate levels, again suggestive of a shift towards aerobic glycolysis [159,172,173].

Neuroimaging and neuropathology

There is now considerable neuroimaging evidence demonstrating impaired blood flow in the cortex and cerebellum in many patients with a diagnosis of CFS [174-176]. Other studies report loss of gray matter volume [177-179]. Interestingly, this phenomenon has also been observed in patients given a primary diagnosis of fibromyalgia which is held by many to be an overlapping illness. Kuchina et al. reported that patients displayed levels of gray matter loss which were some three times greater than expected for their age [180]. Another study using 3-T voxel-based morphometry MRI reported reduced occipital lobe gray and white matter volume in the CFS group [181]. Cook and fellow workers, using functional MRI (fMRI) reported a significant positive association between perceived severity of fatigue and responsiveness in the cingulate frontal, temporal and cerebellar regions [182].

Another research team demonstrated impaired fMRI activation in the dorsolateral, dorsomedial and prefrontal cortices during a fatigue provocation task [183]. Glucose hypometabolism, especially in the prefrontal cortex, has also been demonstrated [184,185]. Finally Barden et al. [186] once again using 3 T MRI-based morphometric analysis reported evidence of astrocyte dysfunction and failure of autoregulatory mechanisms in patients in their trial cohort [186].

Parkinson’s disease

Fatigue in Parkinson’s disease

Pathological fatigue, often described as a state of overwhelming exhaustion not necessarily related to physical effort, is recognized as a major, and possibly the most common, non-motor symptom of Parkinson’s disease [187,188] and often presents an insurmountable problem for patients and their caregivers [189,190]. Profound fatigue is experienced by some 82% of patients with advanced (HY stage 5) disease and the prevalence of fatigue increases with disease severity [191]. Although fatigue has been clearly established as an independent non-motor symptom of Parkinson’s disease, it is often confused with depression or excessive daytime sleepiness in clinical practice [189]. Some authors have actually adduced evidence indicating that fatigue could even be a pre-motor feature of Parkinson’s disease [192,193]. Schifitto et al. reported the presence of fatigue in just over a third of untreated non-depressed patients [194]. Furthermore, several other authors have reported that pathological levels of fatigue occur in non-depressed patients who are also untroubled by sleep problems [187,189].

Immune activation, inflammation and mitochondrial dysfunction

Numerous authors have reported that the serum and CSF of Parkinson’s disease patients contain elevated levels of activated CD4 and CD8 T cells and IL-1β, TNF-α, and IL-2 [195-199]. Increased frequencies of activated CD4+ T cells expressing the programmed death receptor Fas [198] and increased numbers of IFN-γ-producing Th1 cells, decreased numbers of IL-4-producing Th2 cells, and an overall decrease in CD4+CD25+ T cells have been found in the peripheral blood compartment of patients with this illness [200]. Studies have demonstrated that elevated peripheral cytokine production influences the progression of this illness. Parkinson patients display increased serum levels of TNF-α and TNF-α receptor 1 when compared to healthy control subjects, which makes an independent contribution to the pathogenesis of this illness [197,201,202]. It is also noteworthy that elevated plasma IL-6 concentrations significantly and positively correlate with increased risk of developing the illness [203].

Neuropathy and functional central processes

The increased frequencies of activated peripheral and memory T-cell subsets and activated T cells in the substantia nigra indicate the putative roles of T cells in the progression of Parkinson’s disease. There is also evidence that the balance of regulatory or effector T lymphocytes at inflammatory foci can either attenuate or exacerbate neuroinflammation and, hence, the subsequent development of neurodegeneration [13].

The intimate association between Parkinson’s disease and chronic inflammation has been revealed in different studies [204-208]. It is now recognized that chronic systemic inflammation plays a major role in the pathophysiology of Parkinson’s disease [209,210]. Nitrated proteins, DNA damage and lipid peroxidation bear testimony to the presence of elevated oxidative and nitrosative species [211,212]. The detection of extracellular HMGB1 and corrupted protein, DNA and lipid derived entities suggests substantial DAMP activity [213]. The weight of evidence indicates that the engagement of high-mobility group protein B1 (HMGB1) and alpha synuclein plays a major part in exacerbating the pathology of Parkinson’s disease [214,215]. Due to its modified conformation alpha synuclein behaves as a DAMP by activating TLR4 receptors on microglia resulting in the release of a plethora of neurotoxic entities, toxic molecules, including O and NS and proinflammatory cytokines and prostaglandin E2 (PGE2), thereby exacerbating neuro-inflammation [216,217].

Mitochondrial dysfunction in Parkinson’s disease in the shape of Complex I (CI) impairment has been suggested to be one of the fundamental causes of the illness [218,219]. This complex I deficiency is seen in the frontal cortex and substantia nigra in the patients [62], and in peripheral tissues, such skeletal muscle [220-222] and platelets [63,223,224], strongly indicating a widespread reduction in complex I activity in Parkinson’s disease. This defect is likely due to oxidative damage to complex 1 and possibly mis-assembly, as this latter phenomenon has been observed in isolated Parkinson’s disease brain mitochondria [225]. This complex I inhibition can induce the degeneration of neurons via a number of different mechanisms, such as excitotoxicity and increased oxidative stress [226]. A decrease in complex III function has also been reported in the platelets and lymphocytes of patients with this illness [64,223]. An association between the level of impairment of mitochondrial complex III assembly leading to a subsequent increase in ROS production and the development of Parkinson’s disease has also been reported [227]. This elevation in free radical production and release likely stems from the increased leakage of electrons from complex III. An alternative, but not mutually exclusive, explanation is that the inhibition of complex III assembly results in a severe reduction in the levels of functional complex I in mitochondria [228], again leading to an increase in ROS production via complex I deficiency. It is also noteworthy that the complex I and II electron acceptor ubiquinone is also reduced in the mitochondria of patients with Parkinson’s disease [229].

Neuroimaging and neuropathology

An almost bewildering array of neuroimaging abnormalities have been observed in patients with Parkinson’s disease and overall it is now clear that the various manifestations of the disease cannot be attributed to basal ganglia dysfunction alone [230,231]. Numerous studies employing voxel based morphometry have revealed a global pattern of gray matter loss and conformational abnormalities in Parkinson patients [232,233]. These gray matter changes are associated with cognitive and memory impairments which are seen in patients with very early disease [234,235]. Nagano-Saito and others reported that gray matter density displayed a positive and significant correlation in the dorsolateral prefrontal cortex and parahippocampal gyrus [236]. Loss of gray matter volume is apparent in treatment naive patients, once again bearing testimony to the existence of these abnormalities at the earliest stages of the disease [237].

The use of NMR spectroscopy has revealed neurometabolic abnormalities particularly a decrease in N-acetyl aspartate levels [238]. Finally, the use of the same technique has revealed the existence of widespread mitochondrial dysfunction in the brains of people with Parkinson’s disease even in the absence of any overt clinical manifestations [239]. Treatment naïve patients also display glucose hypometabolism in the dorsal pons, putamen and ventral thalamus [240-242]. Positron emission tomography (PET) imaging has revealed cortical hypometabolism in Parkinson’s disease. The severity and topography of glucose hypometabolism in the frontal and occipital cortex seen even in prodromal patients [243] intensifies and involves the lateral parietal and prefrontal cortices [242,244,245] and may also include the medial frontal and occipital regions [243,246] in patients with mild cognitive impairment (MCI). The severity and location of this hypometabolism may reflect the degree and extent of cognitive dysfunction [243,245,247,248]. The widespread cortical hypo-perfusion reported by many authors is also apparent at very early stages of disease and also appears to be related to the development of cognitive dysfunction [246,249,250].

Major depressive disorder

Fatigue in depression

Fatigue of variable severity occurs in practically 100% of people with a diagnosis of depression [251,252]. It is worthy of note, however, that a systematic review reported that almost 80% of patients still experienced chronic debilitating levels of exhaustion following treatment of their depression [253]. This is perhaps to be expected given that several studies have now demonstrated that antidepressants have no positive modulatory effects on fatigue [254-257].Immune activation, inflammation and mitochondrial dysfunction

The existence of increased levels of circulatory proinflammatory cytokines in these patients is now a textbook truism [20]. The picture regarding patterns of cytokine imbalance is complex with elevated levels of anti-inflammatory cytokines often reported [258]. There is copious evidence of chronically activated T cells with Th1, Th2 and Th17 patterns of differentiation [20,259,260]. It is worthy of note, however, that T cells appear to be dysfunctional, displaying an overall pattern of abnormalities consistent with a state of anergy [261]. Until recently, evidence of TLR activation in depression was limited to an animal model [262] but recently a study reported elevated levels of TLR4 in the brains of depressed patients displaying suicidal ideation [263]. Chronic systemic inflammation and oxidative stress play a major role in the etiology of depression [19,20]. Elevated levels of redox-damaged DAMPs, including oxidized low density lipoprotein, oxidized phospholipids, and malondialdehyde (MDA)-adducts are also consistently found in patients suffering from this illness [48]. Compromised epithelial barrier integrity is also a finding in depression and the resulting bacterial translocation into the systemic circulation is intimately involved in the pathogenesis of the disease [20,155]. Mitochondrial dysfunction affects neuronal function, synaptic plasticity, energy metabolism and neurotransmitter release and, hence, it is not surprising that there is increasing evidence that mitochondrial dysfunction and inflammation drive the symptoms of major depression [65,66]. Gardner and Boles highlighted the fact that research has failed to confirm a consistent relationship between serotonin levels and depression and that compromised bioenergetics should become a focus of research into the pathogenesis of the illness [264].

Neuroimaging and neuropathology

Hamilton and fellow workers reported the results of their meta-analysis of studies ultilizing various modalities of functional neuroimaging in patients with depression [265]. These authors concluded that a synthesis of the studies revealed a pattern of higher baseline neural activity in the pulvinar nucleus [265]. They further reported that studies ultilizing negative stimuli demonstrated a significantly greater neural response in certain areas of the brain, such as the amygdala, and lower responses in other regions, such as the prefrontal cortex, possibly indicating impaired contextual processing and reappraisal of visceral inputs [265]. In another meta-analysis, Kempton and others reported that patients with a diagnosis of depression and bipolar disorder displayed increased rates of hyperintensities in subcortical gray matter and increased volume of the lateral ventricles compared to healthy controls [266].

Interestingly, this meta-analysis also revealed distinct differences in neuroimaging abnormalities between depression and bipolar disorder, with the former having reduced rates of hyper-intensities in white matter and smaller basal ganglia and hippocampi compared to bipolar patients [266]. There is evidence that patients in a state of depression display reduced gray matter volume in the hippocampus compared to healthy controls or patients in remission [267]. Other investigators analyzing studies involving voxel based morphometric analysis have reported more widespread loss of gray matter in many different areas of the brain, especially in the prefrontal cortex [268-270]. It is noteworthy that gray matter reduction is evident in patients with first episode depression [271]. Impaired perfusion in frontotemporal regions has been reported [272] and a recent study has reported global cerebral hypoperfusion [273]. Interestingly, the degree of hypoperfusion in the prefrontal cortex correlates positively with the severity of depressive symptoms in patients with Alzheimers disease [274]. Another research group has recently reported that regional cerebral blood flow abnormalities in the prefrontal cortex and anterior cingulate cortices reverse during remission [275]. Glucose hypometabolism has been demonstrated in depressed patients both in the prefrontal cortex [276] and in several other regions [277]. An intriguing connection between glucose hypometabolism was proposed in a study by Hirono and others, who reported a positive significant association with the presence and severity of depressive symptoms in Alzheimer patients and decreased glucose metabolism in the frontal lobe [278]. Finally, the presence of activated microglia in patients suffering from depression has been established via the use of in vivo non-invasive neuroimaging [279].

Systemic lupus erythematosus

Fatigue in SLE

Fatigue is an extremely common and disabling symptom affecting some 80% of patients with SLE [280]. Fatigue severity scores are significantly higher than population norms and similar to levels seen in patients with MS and Lyme disease [281,282]. Chronic debilitating fatigue is a major cause of morbidity in patients with SLE [283], that decreases quality of life [284-286] and increases work disability [287,288]. The aerobic capacity of patients with mild SLE is comparable to that observed in patients with severe cardiopulmonary disease [289-291]. Disease activity appears to be a major factor in the genesis of fatigue although this relationship is not evident in all studies [280,283,292,293].

Immune activation, inflammation and mitochondrial dysfunction

There is extensive evidence of activated T cells in the peripheral immune system of patients with SLE [294]. Elevated levels of proinflammatory cytokines play a key role in the pathophysiology of SLE [295]. Salbry et al. [296] reported a significant positive correlation between levels of TNF-α and IL-6 and objective markers of disease activity [296]. The weight of evidence indicates that significantly elevated levels of proinflammatory cytokines in the systemic circulation also plays a causative role in the development of systemic inflammation [297,298].

The presence of a chronic inflammatory state in people suffering from SLE has been reported by several research teams [28,299]. Wang and colleagues reported a significant positive correlation between elevated markers of O and NS with disease activity in this illness [300]. A range of TLRs are involved in initiating and maintaining the pathology of SLE, including TLR4, TLR3, TLR9 and TLR7 [301,302]. Impaired clearance of apoptopic cells is a pathological feature of SLE and, hence, the blebs and modified cellular contents act as autoantigens and are recognized by the immune system as DAMPS with the resultant activation of TLRs especially TLR4 [303,304]. The impaired clearance of these cells sets off a sequence of biochemical events allowing the escape of extramatrix debris once again acting as an autoantigen and recognized as a DAMP with the consequent activation of TLR4 and, indeed, a range of other TLRs as well [304]. Interestingly, polymorphisms in TLR4 (and CD14) genes are now thought to play a significant role in the etiopathogenesis of SLE. Persistent mitochondrial membrane hyperpolarization, increased O and NS production combined with depleted levels of glutathione and ATP is characteristic of T cells in SLE [67,68]. This environment sensitizes T cells towards necrotic cell death and the consequent release of DAMPS into the blood stream affords a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation [69,305].

Neuroimaging and neurological abnormalities

Neurological symptoms in SLE are commonplace, affecting upwards of 80% of sufferers [32]. These neurological abnormalities occur even in the absence of the various systemic disease manifestations [306]. Voxel based morphometric analysis revealed widespread gray matter volume reduction in patients diagnosed with SLE [307-309]. Other studies have revealed the presence of white matter hyper-intensities, whose prevalence in an individual is predictive of disease progression [309-311]. The presence and severity of fatigue in patients with SLE is associated with white matter hyperintensities [312]. These authors reported that the White Matter Hyperintesity score correlated positively and significantly with fatigue severity [312]. The pathophysiology of ‘neuropsychiatric’ Lupus is mediated by cytokines, complement components and autoantibodies leading to the development of neuroinflammation and, ultimately, apoptosis of neurons and glial cells [313-316]. It is perhaps no surprise that the presence of activated microglia have been confirmed in patients with SLE [34].

Sjogren's syndrome

Fatigue in Sjogren's syndrome

Fatigue and pain are, again, the most common extra-glandular symptoms of Sjogren's syndrome [317,318]. A total of 70% of patients with Sjogren’s syndrome suffer from fatigue and many patients state that fatigue is one of the most disabling symptoms of their disease [319]. There are a number of studies reporting a significant positive association between the severity of fatigue experienced by patients and various surrogate markers of disease activity [320-322]. The fatigue levels are associated with higher sicca symptoms, lower salivary volume, increased serum anti-Sjögren’s syndrome A antigen, immunoglobulin G (IgG) and proinflammatory cytokine levels [323]. Further evidence suggesting cytokine involvement in the genesis of fatigue was provided by Norheim and fellow workers who reported that patients’ fatigue levels were reduced by some 50% following blockade of IL-1β [324].

Immune activation, inflammation and mitochondrial dysfunction

Predictably there is copious evidence demonstrating the existence of a chronically activated innate immune system in patients diagnosed with this illness [325]. There is a wealth of data demonstrating disturbed cytokine networks [326], with cytokines secreted by activated Th1 and Th17 T cells being commonly detected in various blood compartments [327,328]. Epithelial cell activation leading to TLR upregulation is considered by many to be a pivotal early event in the pathogenesis of Sjogren's syndrome [329,330]. A range of TLRs, including TLR2, TLR3 and TLR4, are chronically up-regulated in sufferers of this illness [329,331]. Chronic systemic inflammation is an almost invariant finding in Sjogren's syndrome patients [332]. The existence of chronically elevated O and NS and subsequent oxidative stress has also been repeatedly demonstrated in patients with this disease [70,333]. The link between mitochondrial dysfunction and chronic oxidative stress is now firmly established in Sjogren's syndrome [70].

Neuroimaging and neurological abnormalities

A wide range of abnormalities in the central and peripheral nervous system occur in up to 70% of patients with Sjogren's syndrome, which may precede diagnosis in over 90% of cases [33,334,335]. Those interested in the details of these neurological abnormalities are invited to consult an excellent review by Tobon et al. [33]. There is some evidence that CNS pathology is immune mediated [336] and many patients display abnormalities on MRI with increased signaling intensity in T2 weighted images being the commonly noted finding [337,338]. These white matter hyperintensities (WMH) are indicative of widespread hypoperfusion [336,339-341]. Voxel based morphometry has once again revealed a global pattern of gray matter volume loss [340,342] and very recently loss of cerebral white matter was observed for the first time [343].

Rheumatoid arthritis

Fatigue in rheumatoid arthritis

Patients with rheumatoid arthritis commonly complain of severe intractable fatigue with prevalence rates of up to 80% depending on definitions of fatigue used [344]. A study employing a fatigue measuring instrument reported that 40% of patients with rheumatoid arthritis experienced unremitting severe fatigue of the same level and pattern as fatigue experienced by patients with a diagnosis of chronic fatigue syndrome [345]. From a patient perspective fatigue is often described as extreme, unremitting and unrelated to activity and is associated with a failure to perform routine daily activities and non-refreshing sleep which, when considered together, are more debilitating than pain [346,347]. Reducing inflammation with disease modifiers significantly reduces fatigue [348]. Considerable evidence now exists demonstrating that the severity of fatigue experienced by patients suffering from this disease correlates significantly and positively with levels of disease activity [349,350].

Immune activation, inflammation and mitochondrial dysfunction

Numerous research teams have adduced evidence of a chronically activated immune system in rheumatoid arthritis patients as evidenced by significantly increased serum Th1, Th2 and Th17 cytokines [351-353]. Blockade of Th1 and Th17 cytokines can result in significant clinical benefit in patients with rheumatoid arthritis, strongly indicating their role as causative agents in the disease [354,355]. The frequency of Th17 T cells and associated cytokines strongly correlates with a poor prognosis which again suggests that these entities play a major causative role [356]. There is also good evidence that the use of biologic agents results in significant improvements in fatigue, strongly implicating elevated levels of these species in the genesis of intractable fatigue in patients with rheumatoid arthritis [357,358].

There is also considerable evidence demonstrating the activation and upregulation of TLRs in this disease with upregulated TLR2, TLR3 and TLR4 being commonplace findings [359-361]. Rheumatoid arthritis is recognized as being a systemic inflammatory condition [359] and chronic inflammation and accompanying oxidative stress play a causative role in the illness [362,363]. Perhaps unsurprisingly then, it has been demonstrated that levels of inflammation correlate positively with measures of disease activity [364]. The positive association between inflammation and fatigue genesis is evidenced by the fact that reducing inflammation with disease modifiers significantly reduces fatigue [348]. The effector molecules of chronic inflammation and oxidative stress can induce irreversible genetic changes and one such change, mutations in p53, has been suggested as a ‘turning point’ in converting a state of chronic inflammation into chronic disease [365]. There is evidence of somatic mutations in the mitochondrial DNA (mtDNA) within synoviocytes of rheumatoid arthritis patients which may confer immunogenicity on mtDNA derived proteins which consequently adopt the character of DAMPS and be one of such entities thought to play a major role in the etiopathogenesis of this disease [366]. A positive association has been reported in these cells between the extent of these mutations and the expression of cyclo-oxygenase 2 (COX-2), prostaglandin (PG)E2 and IL-8 [367]. The existence of these inflammatory markers is highly suggestive of NO-induced inhibition of complex III and V of the electron transport chain [72,368].

Neuroimaging and neuropathology

There is no direct evidence supporting the existence of chronically activated microglia and neuroinflammation in patients with rheumatoid arthritis, but neurological sequelae are commonplace and the role of chronic systemic inflammation in establishing such sequelae is accepted [35]. Wartoloska et al. reported widespread cortical atrophy in their patients with rheumatoid arthritis using unbiased voxel morphometric analysis and a pattern of increased gray matter density in subcortical areas notably the basal ganglia with the latter finding being suggestive of decreased dopamine levels [369]. An earlier MRI imaging study by Bekkelund and fellow workers also detected cortical atrophy in rheumatoid arthritis patients but only in those with longstanding disease [370].

Cross-talk peripheral and CNS inflammation

There is now copious evidence that chronic or intermittent inflammation, as observed in the abovementioned systemic disorders, can worsen or trigger neuroinflammatory or neurodegenerative processes via the induction of primed microglia [8,12]. Briefly, prolonged or intermittent peripheral inflammation and immune activation act to prime microglia which thereafter become exquisitely sensitive to future inflammatory stimuli [8]. Once microglia have achieved this sensitized status, subsequent peripheral inflammation and proinflammatory cytokine production mediated by a number of insults (for example, biotoxin exposure or pathogen invasion) provokes an exaggerated response from microglia and the production of excessive concentrations of neurotoxic molecules, such as nitric oxide, peroxinitrite, prostaglandins, cyclo-oxygenase 2 and cytokines [6,7]. The secretion of these neurotoxins and alarmins leads to the activation of astrocytes and the combined activation of these glial cells provokes dysregulation of brain homeostasis, development of chronic neuroinflammation and neurotoxicity. Both humoral and neuroendocrine routes mediate proinflammatory signaling to the brain. The neural route operates via the dorsal motor nucleus of the afferent vagus nerve [6]. The humoral route is facilitated by circulating proinflammatory cytokines that communicate their presence to the brain via direct and indirect routes.

Such pathways involve engagement with specific transporters in the blood brain barrier (BBB), the activation of endothelial cells and macrophages, creating a mirror pattern of production on the adluminal side of the BBB, and passive diffusion into areas of the brain lacking a functional BBB (for example, circumventricular organs) and thereafter into the glial limitans [1]. The cumulative effects of proinflammatory cytokines and activated astrocytes cause disruption of the BBB allowing abnormally high numbers of activated T cells and B-cells to circulate between the peripheral immune system and the brain, acting as more channels of communication between the peripheral and central immune system [13]. It should be noted that cytokines are able to diffuse from the CNS into the bloodstream as well [13]. Finally, the presence of proinflammatory cytokines in the brain activates the hypothalamus instigating the cholinergic anti-inflammatory pathway designed to terminate the immune response [1,6]. These processes are depicted in Figure 2.

All disorders reviewed here, except Parkinson’s disorder, are more frequent in women than in men. For example, in patients with rheumatoid arthritis a four to five greater incidence is found in women than in men when less than 50 years old, whereas these differences are less pronounced in 60- to 70-year old individuals. The female predilection is also observed in depression, CFS, MS, Sjogren’s syndrome and systemic lupus erythematosus [371-375]. In Parkinson’s disorder the male/female incidence rate ratio is 1.6 to 1 [376]. One main difference between Parkinson’s disease and the other disorders discussed here is that the autoimmune component is less pronounced in Parkinson’s disease. An increased incidence rate in women is observed in most autoimmune disorders [371]. Nevertheless, also in Parkinson’s disease autoantibodies are observed and they are associated with specific symptom profiles, including depression [377]. It is argued that these sex-related differences in incidence may be explained by endogenous sex-hormones.

Estrogen, progesterone and testosterone play important immunomodulatory roles and influence the quantity and pattern of cytokine secretion by antigen presentation cells and T lymphocytes and immunoglobulin production by B cells. Sex hormones also regulate the Th1/Th2 balance of the immune system, the production of regulatory T cells and the functionality of granulocytes and natural killer cells [378,379]. An interested reader is referred to an excellent review by [380] for a detailed consideration of the mechanistic effects of sex hormones on individual classes of immune cells. In the light of the discussion above, it also seems noteworthy that estrogen is neuroprotective in many animal models of neuroimmune and neurodegenerative disorders essentially by down regulating the expression of neuroinflammatory genes in glial cells, such as those coding for elements of the complement system, proinflammatory cytokines and TLRs [381]. Thus, excessive estrogens but less androgens may favor activation of B cells, a Th2-like response and increased numbers of autoimmune cells and, thus, autoimmune responses [371]. Nevertheless, the precise effects of sex- or gender-related factors on the increased incidence of autoimmune-related disorders has remained elusive. Future research should delineate not only sex but also gender-related effects according to the gendered innovations approach [382].

These parameters and elevated number of circulating T cells seen in premenopausal women may be one reason for the powerful prolonged activation of inflammatory pathways and adverse reactions to aluminum adjuvants seen in women following administration of a range of vaccines [383,384]. The engagement of TLR receptors by aluminum, as well as the activation of the NLP3 inflammasome, could create a state of chronic inflammation and oxidative stress in a person with functional polymorphisms in immune genes as discussed above and, hence, could be a cause of Autoimmune Inflammatory Syndrome Induced by Adjuvants (ASIA), alternatively known as Schoenfield’s Syndrome [385-387]. The activation of TLR4 by silicon [388] could also explain the connection of this element with the development of ASIA and the chronic activation of TLRs can potentially explain many environmental contributions to the ‘mosaic of autoimmunity’ [389].

Sex effects may also determine responsivity to drug therapy as, for example, in MS. Thus, postmenopausal women are poorer responders to rituximab than men of the same age [390,391]. This might seem a little counter intuitive from the frame of reference that rituximab exerts its effects mainly on the B cell population and that B cell levels do not appear to differ in postmenopausal women and age equivalent men to any significant extent [392]. However rituximab also exerts modulatory effects on the T cell compartment [393]. Numerous researchers have reported that the clinical benefits seen following the use of rituximab in rheumatoid arthritis and other autoimmune conditions are associated with the antibody’s capacity to increase the expression of FOXP3 [394], suppress the expression of retanoic acid-like orphan receptors ultimately suppressing the production of Th17 T cells and IL-17 [395] and reducing the expression of cytokines by Th1, Th2 and Th17 T cells [396]. It is possible that the Th2 shift in the immune system seen in postmenopausal women negates the benefits of rituximab on a Th1/Th17 biased immune system [392]. The positive benefits of rituximab and natalizumab on MS [84,85] is probably most easily explained by the modulatory effects of rituximab and, likely, natalizumab on the T cell compartment as well as their well-documented effects on B cell depletion.

Summary and conclusion

Figure 3 shows a diagram illustrating the causal links being described in the above sections synthesizing the significant pathways that lead to secondary fatigue in these different neurodegenerative and systemic (auto)immune disorders. There is clear evidence of a positive relationship between fatigue severity and levels of disability in MS. It is of interest that levels of peripheral inflammation, oxidative stress and TNF-α also display a positive correlation with objective markers of disease activity and disability levels and that levels of proinflammatory cytokines correlate positively with levels of fatigue. The existence of gray matter atrophy before the advent of white matter abnormalities, and the existence of metabolic abnormalities before the advent of gray matter pathology, rather argues against the proposition that the chronic peripheral immune activation and oxidative stress seen in early disease is secondary to the release of inflammatory mediators from the CNS. These observations, coupled with data demonstrating that the severity of neuro-inflammation depends on the level of peripheral immune activation and that inflammation drives the development of disease, emphasizes the likely causative role of peripheral pathology.

The strong association between the severity of fatigue and disability and the level and geographical distribution of glucose hypometabolism and gray matter hypoperfusion strongly indicates that these elements are driven by generic rather than disease specific pathology. These kinds of generic abnormalities are also evident in Parkinson’s Disease where peripheral immune activation, oxidative stress, GM atrophy and widespread glucose hypometabolism are all evidenced in the very earliest stages of disease development. It is also noteworthy that the prevalence of severe intractable fatigue increases with the degree of disease progression and that the degree of peripheral inflammation and levels of proinflammatory cytokines are predictive of disease development and severity. When viewed as a whole these observations also support the view that severe intractable fatigue results from processes which are not disease specific but involved in disease pathogenesis.

The existence of chronic peripheral inflammation and immune activation together with GM atrophy and glucose hypometabolism in patients with first episode depression is now a textbook truism. Interestingly, the pattern of neuroimaging abnormalities and GM pathology appears to be quite distinct from that seen in patients with neuroimmune and autoimmune diseases for reasons which are not yet clear. This pattern of peripheral inflammation and immune activation is also found in autoimmune diseases with levels of oxidative stress and proinflammatory cytokines having a causative role in the pathophysiology of SLE and displaying positive correlations with objective markers of disease severity. This is also true of patients with Sjogren's syndrome where objective markers of disease activity are reduced by cytokine blockade. There is also evidence demonstrating that the severity of fatigue is associated with the degree of white matter hyperintensities in people with SLE and evidence that the neuropathology in Sjogren's syndrome is immune mediated.

The widespread mitochondrial dysfunction seen in people with autoimmune diseases could also make a significant contribution to the development of fatigue. Widespread mitochondrial dysfunction, in otherwise normal tissue, is also seen in patients with MS, Parkinson’s disease and in many patients with apparently idiopathic fatigue. Given that many such patients also display evidence of peripheral immune activation, oxidative stress, gray matter pathology, glucose hypometabolism, hypoperfusion and metabolic abnormalities in the prefrontal cortex, basal ganglia and elsewhere, it would seem reasonable to investigate all such patients for the presence of these abnormalities. Standard MRI is unlikely to be helpful but other approaches discussed in the main body combined with serum measures of immune activation and oxidative stress may well bear fruit.

As these mechanisms are extensively inter-related, it should be underscored that without a solid prospective timeline and known systems biomedicine, it has remained difficult to distinguish causation from association. Therefore, future research should delineate: 1) the overwhelmingly complex and dynamic interactions between these different pathways and the intracellular networks that modulate them; and 2) the multifactorial triggers that cause secondary fatigue by activating the networks/pathways in those disorders, including viral and bacterial infections, bacterial translocation, psychosocial stressors, exposure to adjuvants, nicotine dependence, sex- and gender-related factors, and so on. Towards this end, a systems biomedicine approach is essential to delineate the genetic and molecular signature of fatigue in these disorders and the non-linear interactions between the many pathways, networks, and trigger and genetic factors that underpin secondary fatigue.

Multi-targeting these interlinked dysfunctions may show benefit in these diseases. For example, a number of antioxidant compounds have demonstrated efficacy in modifying pathways leading to chronic inflammation, oxidative stress and immune dysregulation at relatively high doses for a long duration [7]. N-acetyl-cysteine is an example of a multi-target therapeutic approach having the capacity to decrease the levels of ROS/RNS, increase the levels of cellular antioxidants, such as reduced glutathione, and normalize the production of proinflammatory cytokines and immune cell functions [397]. This supplement has demonstrated the capacity to improve fatigue and disease activity in SLE, CFS and major and bipolar depression [7,398]. Omega-3 polyunsaturated fatty acids (PUFAs) and zinc are also very effective antioxidants and anti-inflammatory compounds and supplementation has produced clinical benefit in patients diagnosed with depression and chronic fatigue syndrome [7,399,400]. Omega-3 PUFAs also show a clinical efficacy in SLE and rheumatoid arthritis [398,401,402].

Curcumin, another nutraceutical with anti-inflammatory and antioxidative effects, is useful in the treatment of depression and rheumatoid arthritis [403,404]. Coenzyme Q10 is another powerful antioxidant and anti-inflammatory compound which also has positive effects on mitochondrial function and which displays disease modifying effects in Parkinson’s disease and produced clinical benefit in patients with a diagnosis of CFS [56]. Other approaches aimed at upregulating antioxidant defenses include N acetylcysteine, methylfolate and dimethyl fumarate, with the latter displaying disease modifying properties in MS [140]. Methylfolate produces a similar quantum of benefit in MDD as antidepressants and can often be effective in treatment-resistant depression [140].It is concluded that there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage. (Emphasis added.)____________________

Funding: There was no specific funding for this specific study.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Competing interests: The authors declare that they have no competing interests.

Authors’ contributions: All authors contributed equally to the paper. All authors read and approved the final manuscript.

Columbia University has published the second of two significant studies examining immune system markers in ME/CFS. The study, "Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome," was published in Molecular Psychiatry, a top-ranked journal in the field of neuroscience.

The first study, "Distinct plasma immune signatures in ME/CFS are present early in the course of illness" (February 27, 2015), showed that pro-inflammatory cytokines were elevated in the early phase of the disease, but depressed in later stages. After examining cerebrospinal fluid in long-term patients, the Columbia research team found a similar decrease in pro-inflammatory cytokine IL-1 signaling.

What is interesting about the cerebrospinal fluid study is that patients showed an increase in a chemokine called CCL11 (eotaxin).

Eotaxin is a chemical involved in stimulating eosinophils, immune molecules that are implicated in allergic responses. Studies have shown that increased eotaxin reduces cognitive performance. Particularly affected are spatial navigation and the processing of short into long-term memory (learning). These are both functions of the hippocampus, a small organ in the limbic system.

In his book, The Limbic Hypothesis (1993), Dr. Jay Goldstein proposed the damage to the limbic system was the driving force behind ME/CFS. Research conducted since then has repeatedly confirmed Dr. Goldstein's theory. Now, evidence is mounting that the damage is caused by an autoimmune response.

The Columbia researchers concluded that their results:"...indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity."_________________________________

Press Release: Columbia University's Mailman School of Public Health, March 31, 2015. Scientists at Columbia University's Mailman School of Public Health have identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction - frequently described by patients as "brain fog" - as well as new hope for improvements in diagnosis and treatment.

In the study published in Molecular Psychiatry, Mady Hornig, MD, and colleagues used immunoassay testing methods to measure the levels of 51 immune biomarkers called cytokines in the cerebrospinal fluid of 32 people with ME/CFS for an average of seven years, 40 with multiple sclerosis, and 19 non-diseased controls. The researchers found that levels of most cytokines, including the inflammatory immune molecule, interleukin 1, were depressed in individuals with ME/CFS compared with the other two groups, matching what was seen in the blood study in patients who had the disease for more than three years. One cytokine - eotaxin - was elevated in the ME/CFS and MS groups, but not in the control group.

"We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system," says Dr. Hornig, professor of Epidemiology and director of translational research at the Center for Infection and Immunity at the Mailman School. "These immune findings may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog."

Implications for Diagnosis and Treatment

"Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease," adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity. There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.

A large-scale autopsy study performed by Johns Hopkins has revealed that the brains of people with autism show chronic inflammation produced by microglial activation. This study echoes recent findings by Nakatomi et al. showing microglial activation in the brains of people with ME/CFS.

Excitotoxicity has been put forth as a mechanism of ME/CFS by a number of clinicians and researchers, including Drs. Paul Cheney, Jay Goldstein, Morris and Maes, Martin Pall, and, most recently, Jarred Younger.

What are the implications of this study for ME/CFS? As many have stated, it is clear that there is a connection between neuro-inflammation and a number of illnesses that show CNS and immune abnormalities. This study provides anatomical proof of inflammation in the brains of one of the illnesses on the neuro-immune spectrum, which opens the door for badly needed autopsy studies on ME/CFS patients, particularly those with severe cases. ___________________

Brain inflammation a hallmark of autism, large-scale analysis shows

By Shawna Williams

Press Release: Johns Hopkins, December 10, 2014. While many different combinations of genetic traits can cause autism, brains affected by autism share a pattern of ramped-up immune responses and related inflammation, an analysis of data from autopsied human brains reveals.

The study, a collaborative effort between Johns Hopkins and the University of Alabama at Birmingham, included data from 72 autism and control brains. It was published online last week in the journal Nature Communications.

"There are many different ways of getting autism, but we found that they all have the same downstream effect," says Dan Arking, an associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. "What we don't know is whether this immune response is making things better in the short term and worse in the long term."

The causes of autism, also known as autistic spectrum disorder, remain largely unknown and are a frequent research topic for geneticists and neuroscientists. But Arking had noticed that for autism, studies of whether and how much genes were being used—known as gene expression—had thus far involved too little data to draw many useful conclusions. That's because unlike a genetic test, which can be done using nearly any cells in the body, gene expression testing has to be performed on the specific tissue of interest—in this case, brains that could only be obtained through autopsies.

To combat this problem, Arking and his colleagues analyzed gene expression in samples from two different tissue banks, comparing gene expression in people with autism to that in controls without the condition. All told, they analyzed data from 104 brain samples from 72 individuals, the largest data set so far for a study of gene expression in autism.

Previous studies had identified autism-associated abnormalities in cells that support neurons in the brain and spinal cord. In this study, Arking says, the research team was able to narrow in on a specific type of support cell known as a microglial cell, which polices the brain for pathogens and other threats. In the autism brains, the microglia appeared to be perpetually activated, with their genes for inflammation responses turned on.

"This type of inflammation is not well understood, but it highlights the lack of current understanding about how innate immunity controls neural circuits," says Andrew West, an associate professor of neurology at the University of Alabama at Birmingham who was involved in the study.

Arking notes that, given the known genetic contributors to autism, inflammation is unlikely to be its root cause. Rather, he says, "This is a downstream consequence of upstream gene mutation."

The next step, he says, would be to find out whether treating the inflammation could ameliorate symptoms of autism.

Other authors on the study are Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader, and Jianan Zhan, all of The Johns Hopkins University. The study was funded by the Simons Foundation and the National Institute of Mental Health.

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About me:I'm a 25-year veteran of CFIDS. I know what it is like to be bedbound for long stretches of time. I also know what it is like to recover, and to relapse. But this blog is not about my personal experience. It is intended to be a resource - a collection of anything that might be helpful to the CFIDS community: book reviews, advice, CFIDS news, research, advocacy, opinion, who's who in our community, fundraising... and occasionally a bit of humor.

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